Terapie antidiabetiche e tumori
Marco Gallo SCDU Endocrinologia Oncologica AOU Città della Salute e della Scienza di Torino Molinette - COES
Torino, 23 gennaio 2015
In ottemperanza alla normativa ECM ed al principio trasparenza delle fonti di
finanziamento e dei rapporti con soggetti portatori di interessi commerciali in
campo sanitario, dichiaro che negli ultimi due anni non ho avuto rapporti diretti
di finanziamento con soggetti portatori di interessi commerciali in campo
sanitario
Marco Gallo
DICHIARAZIONE CONFLITTO D’INTERESSE DOCENTI
Insulina e analoghi
Torino, 23 gennaio 2015
“especially in T2DM, the potential harm of glargine must be weighed against rather minor potential therapeutic advantages”
Professor Edwin Gale Editor of Diabetologia
from 2003-2010
M Gallo Torino, 23 gennaio 2015
quality of data for analyses missing relevant basal informations (risk
factors, comorbidities, cancer history, etc.)
increased risk of cancer observed in pts. using glargine only, not confirmed in those treated with glargine + other insulins
short duration of follow-up
insulin doses
therapy variations during follow-up
inclusion of probably pre-existing cases of cancer diagnosed shortly after insulin initiation
statistical management prescription bias:
– pts. receiving prescriptions for different therapies might differ for clinical characteristics, potentially accounting for diversities in cancer incidence
cumulative exposure
adjustment for a limited number of confounders
methodological limitations
Torino, 23 gennaio 2015
M Gallo Torino, 23 gennaio 2015
omologia tra IR e IGF-IR 45-65%
60-85%
recettore insulinico e tumori
Frasca F et al.; Arch Physiol Bioch 2008
Mathieu MC et al; Proc Assoc Am Phys 1997
M Gallo Torino, 23 gennaio 2015 Frasca F et al.; Arch Physiol Bioch 2008
M Gallo Torino, 23 gennaio 2015
recettore insulinico e tumori
M Gallo Torino, 23 gennaio 2015
modifying the insulin molecule not only changes its metabolic effects, but can also alter its mitogenic and antiapoptotic potency
Lispro: receptor-binding domain not affected Aspart: receptor-binding affinity similar to human insulin Glulisine: binding affinity similar to native human insulin Glargine: insulin receptor affinity similar to that of human insulin Detemir: binding affinity reduced (interference of albumin)
M Gallo Torino, 23 gennaio 2015
X10 (AspB10): primo analogo rapido sviluppato “But then came the discovery that halted any
future clinical development of insulin X10.” • affinità di legame IR: 200-400% vs insulina umana • affinità di legame IGF-1R: 600% vs insulina umana
X10 is now recommended by EMA as the positive control in insulin analogue mitogenicity studies
M Gallo Torino, 23 gennaio 2015
• aspart/lispro do not differ substantially from human insulin, nor from each other
• glargine more potent than human insulin/detemir in activating IR-B and IGF-1R
Growth Horm IGF Res 2010
M Gallo Torino, 23 gennaio 2015
M Gallo Torino, 23 gennaio 2015
• metanalisi di 21 RCT sponsorizzati su 8693 pz • confronto vs NPH o glargine OR di sviluppare neoplasie
– significativamente inferiore vs NPH – n.s. inferiore vs glargine
• (mediana di esposizione: 24 settimane)
M Gallo Torino, 23 gennaio 2015 Mannucci E. et al. Diabetes Care 2010
Nested case-control study
– cohort of 1340 insulin-treated T2DM pts – follow-up > 6 yy – 112 incident cancer cases vs. 370
matched controls endpoint: long-term association of
different insulin analogues with cancer incidence
adjusted for: comorbidities, exposure to metformin, and doses of each type of insulin
Previous studies limitations: - limited information on comorbidities - short duration of observation - inclusion of probably pre-existing cases of cancer diagnosed shortly after the initiation of insulin - failure to discriminate between basal and prandial human insulin
M Gallo Torino, 23 gennaio 2015
results: higher mean daily dose of glargine in case vs. control subjects (p =,036)
incident cancer associated with a dose of glargine >/= 0.3 IU/kg/day (both sexes)
no association between incident cancer and insulin doses was found for human insulin or other analogues
after adjusting for confounders, lispro was associated with a marginally lower risk of cancer, which was not confirmed after exclusion of cases occurring within the first 12 months of observation
adjusted for comorbidity, exposure to metformin, and doses of other types of insulin
dosages should always be considered when assessing the possible association of insulin
and its analogues with cancer
Mannucci E. et al. Diabetes Care 2010
M Gallo Torino, 23 gennaio 2015 Monami M. et al. Diabetes Care 2011
nested case-control study
– cohort of 1340 insulin-treated T2DM pts – follow-up > 6 yy – 112 incident cancer cases vs. 370
matched controls endpoint: to assess the effect of
metformin on cancer incidence in a consecutive series of insulin-treated patients
results: after adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not SUs, was associated with reduced incidence of cancer
maintain metformin, unless contraindicated,
in all insulin-treated T2DM patients
M Gallo Torino, 23 gennaio 2015
• large population-based cohort study: 19,337 incident insulin users [878 developed cancer]
• association between glargine, other analogues, and cancer vs human insulin
• cumulative duration of drug use
Diabetologia 2011
M Gallo Torino, 23 gennaio 2015
• glargine (& other analogues) associated with a lower risk of malignancies in general vs human insulin HR 0.75 (95% CI 0.71, 0.80)
Glargine: • significantly lower risk of colon cancer • however, increased risk for breast cancer
HR 1.58 (95% CI 1.22, 2.05)
• no dose–response relationships identified Insulin analogues other than glargine: • No increased risk of breast cancer
Diabetologia 2011
M Gallo Torino, 23 gennaio 2015
large cohort study (UK General Practice Research Database)
– 15,227 insulin-treated T2DM women > 40yy – follow-up 8 yy – 246 incident breast cancer cases – adjustment for: age, BMI, cancer history, HRT
use, smoking, alcohol, HbA1c, duration of DM and of insulin use, other antidiabetics
– exclusion of 1st year of follow-up results:
glargine not associated with increased risk of breast cancer during first 5yy of use
the risk tended to increase after 5 yy (3x)
significantly increased risk for women on insulin therapy before starting glargine
M Gallo Torino, 23 gennaio 2015
M Gallo Torino, 23 gennaio 2015
12.537 pz (età media 63.5aa) con fattori di rischio CV e: • IFG-IGT • T2DM (durata di malattia ~5,5 anni)
randomizzati tra: • terapia con glargine (target: FBG </=95mg/dl) • standard care
outcome coprimari: IM non fatale, ictus non fatale, morte per cause CV (microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups)
mediana di follow-up: 6,2 anni nessuna differenza significativa in termini di
• outcome cardiovascolari • neoplasie (HR 1.00)
M Gallo Torino, 23 gennaio 2015
“However, on the basis of the findings from epidemiological studies and the latest welcome and overdue pharmacokinetic data, the chapter on whether insulin glargine per se is an independent risk factor for cancer should now be closed.”
Owens DR., Diab Care 2012
M Gallo Torino, 23 gennaio 2015
diabete d’insorgenza recente o pre-diabete o mediana della dose di glargine: 0.31-0.4U/kg o differenza FBG 29mg/dl; HbA1c 0.3%
~27-47% dei pazienti trattati anche con metformina
al baseline o entro la fine dello studio!
elevato drop-off dopo 6,2 anni
elevata contaminazione tra i bracci
breve periodo di esposizione
M Gallo Torino, 23 gennaio 2015
systematic review and meta-analysis of 27 cohort and 15 case-control studies in T1DM/T2DM: – 42 examining risk of any cancer – 27 examining risk of site-specific cancers
• few studies available for most cancer sites • 8 providing estimates by dose or duration
Curr Drug Saf. 2013
M Gallo Torino, 23 gennaio 2015
Insulin vs No Insulin • increased risk for pancreas, liver, kidney, stomach
and respiratory cancer • decreased risk for prostate cancer Insulin vs Non-Insulin Antidiabetics • increased risk for any, pancreatic and CRC Glargine vs Non-Glargine Insulin • increased risk for breast cancer • decreased risk for colon cancer
Curr Drug Saf. 2013
M Gallo Torino, 23 gennaio 2015
• associazione tra esposizione a monoterapia insulinica (dal 2000 in poi) e – mortalità per tutte le cause – MACE – incidenza tumori
• studio retrospettivo su 6584 pz con T2DM • UK Clinical Practice Research Datalink • follow-up medio 3,3 anni (minimo 6 mesi) • dose media: 0.75 U/kg/die
Diabetes Obes Metab. 2014 Nov 14
M Gallo Torino, 23 gennaio 2015
Diabetes Obes Metab. 2014 Nov 14
M Gallo Torino, 23 gennaio 2015
rate of progression of solid tumour cancers in people with diabetes receiving alternative glucose-lowering therapies
sulfonylurea monotherapy
sulfonylurea plus metformin
insulin-based therapy
no diabetes treatment exposure
metformin monotherapy
• population-based retrospective cohort study on 10,300 users of metformin or sulphonylureas
• follow-up 5.4 years
limits: no information on glycemic control, BMI, or smoking status
M Gallo Torino, 23 gennaio 2015
studio osservazionale prospettico di coorte olandese (1998-1999) su relazione tra metformina e mortalità tumorale.
1353 pazienti, follow-up medio 9,6aa
l’impiego di metformina (289 pazienti) è risultato associato ad una minore mortalità per cancro nel T2DM
effetto protettivo dose-dipendente
HR 0.43 (95%IC 0.23-0.80)
Landman GW et al. Diabetes Care 2010
M Gallo Torino, 23 gennaio 2015
studio osservazionale su relazione tra terapie antidiabetiche e mortalità (tumorale e non) in pz con T2DM
3685 pz, follow-up medio 4,5aa
l’impiego di metformina è risultato associato a una minore mortalità per cancro nel T2DM (HR 1.56)
effetto protettivo dose e tempo-dipendente (ogni 5 anni di trattamento associato a riduzione R mortalità tumorale 0,73)
Diab Ob Metab 2011
M Gallo Torino, 23 gennaio 2015
metformina e neoplasie: studi clinici
limite principale: utilizzo della metformina con T2DM in fase precoce, mentre gli altri farmaci vengono introdotti successivamente, quando vi è già stato un periodo più o meno lungo di inadeguato compenso glicemico
DeCensi A et al, Cancer Prev Res 2010
M Gallo Torino, 23 gennaio 2015
metanalisi di 6 studi osservazionali (21.000 pz diabetici)
M Gallo Torino, 23 gennaio 2015
attivazione della via di segnale LKB1-AMPK
o effetti antiproliferativi/antiangiogenici
riduzione dell’espressione di HER-2
effetti sulla fase G0-G1 del ciclo cellulare
riduzione dei livelli di VEGF, PAI-1, TNFα, TPA (angiogenesi, flogosi)
induzione dell’apoptosi (p53)
effetti immunomodulanti sulle cellule CD8+
effetto sulle cellule staminali tumorali
metformina & tumori meccanismi proposti
effetti sull’iperglicemia
o Inibizione della gluconeogenesi
effetti sul peso
aumento della sensibilità insulinica
riduzione dei livelli di vitamina B12?
M Gallo Torino, 23 gennaio 2015
M Gallo Torino, 23 gennaio 2015
current evidence suggests that there is a real possibility that metformin may have beneficial effects on breast cancer outcome
metformin is an inexpensive and safe drug effects on pts w/o hyperinsulinemia?
“We believe the science underlying such a trial is
strong, the novelty of the intervention is high, and the potential for benefit is large”
M Gallo Torino, 23 gennaio 2015
Consensus statement su
prevenzione ca mammario
– stile di vita
– BMI
– attività fisica
– moderato consumo alcol
– farmaci
Cuzick J et al., Lancet 2011
“In view of these promising data, the potential usefulness of this drug for many diseases, and the good side-effect profi le, metformin deserves to be given high priority
for further clinical research.”
Lancet Oncol. 2011
Compared with patients with metformin as first diabetes medication, no increased
risks of cancer of all sites were found in patients with other first diabetes
medication, i.e., either sulfonylurea, insulin, or other medication but metformin.
M Gallo Torino, 23 gennaio 2015
glitazoni
• reduce insulin resistance and hyperinsulinemia
• promote terminal cell differentiation (adypocites)
• PPARγ effect on oncogenesis pathway: • inhibit tumor growth by inducing cell cycle arrest? • induce apoptosis? • anti-angiogenic mechanism?
• experimental antitumoral effects on: • colon carcinoma cell culture (HT-29) • adenomatous polyposis (mice) • glyoma (in vivo) • lung cancer cell cultures (NSCLC H841, A549, abd PC14) • prostate cancer cell culture (LNCaP) • thyroid cancer cell culture • HCC cell culture • liposarcoma
M Gallo Torino, 23 gennaio 2015
PPARγ agonists: • Alter cell proliferation rates and differentiation in
uroepithelial tissue • Increased risk of bladder cancer • May be prevented with diet? (acid milieu of urine) • Increased in situ cancer rate:
– greater surveillance? – effect on early stages of development?
M Gallo Torino, 23 gennaio 2015
Revisione sistematica e metanalisi di RCT e studi osservazionali 2.600.000 pz con T2DM complessivi RR pioglitazone: 1,22 (IC95% 1,07-1,39)
Colmers IN et al., 2012
Torino, 23 gennaio 2015 M Gallo
Incidenza di tumore della vescica nei diabetici in prospettiva
Incidenza per 100.000 pazienti diabetici-anno
Eventi cardiovascolari maggiori 5000
Decessi cardiovascolari 1330
Neoplasie maligne 1308
Tumori colo-rettali 198
Tumori polmonari 159
Tumori della vescica 69
• NNH studio CNAMTS 10.620 K vescica • NNH studio KPNC 7874 K vescica • NNT studio PROactive 144 MACE
M Gallo Torino, 23 gennaio 2015
pioglitazone & carcinoma della vescica
Diabetologia 2014 Dec 7
M Gallo Torino, 23 gennaio 2015
pioglitazone & ca vescica: “pearls for practice” • Prima d’iniziare trattamento con pioglitazone, valutare la
presenza di fattori di rischio per ca vescica – età – fumo – esposizione a tossici lavorativi o farmaci (es. ciclofosfamide) – RT pregressa sull’area pelvica
• Escludere pazienti con anamnesi positiva per ca vescica • Indagare qualunque ematuria, prima d’iniziare terapia con
pioglitazone • Prestare attenzione a comparsa di ematuria (da monitorare),
disuria o urgenza minzionale durante il trattamento
M Gallo Torino, 23 gennaio 2015
Sequence of events in rodents after long-term GLP-1 receptor agonist dosing:
1. GLP-1 receptor agonists bind to and activate GLP-1 receptors on C-cells
2. GLP-1 receptor activation on C-cells induces calcitonin release
3. Continued calcitonin secretion is followed by increased synthesis
4. Persistent stimulation of calcitonin synthesis is followed by C-cell
hyperplasia in rodents
5. Long-term C-cell hyperplasia may lead to C-cell neoplasia in rodents
Knudsen LB Endocrinology 2010
GLP1-RA e ca midollare della tiroide
M Gallo Torino, 23 gennaio 2015
1. Humans have far fewer C-cells than rodents
2. GLP-1 has effects in rodent, but not human, C-cells
cAMP, cyclic adenosine monophosphate
Species C-cell density
(n/mm thyroid)
Difference to humans
in fold
Human 10±26 –
Monkey 23±10 2
Mouse 216±62 22
Rat 449±222 45
Rodents
Humans
GLP-1 receptor density (n/cell)
1600–13,000 0–105
cAMP generation (liraglutide EC50, pM) 5800 Not
detected
Calcitonin release (liraglutide EC50, pM)
5300 Not detected
RODENTS VS HUMANS DENSITY OF GLP 1 RECEPTORS
Knudsen LB Endocrinology 2010
GLP1-RA e ca midollare della tiroide
M Gallo Torino, 23 gennaio 2015
CT was measured every 3 months in >5,000 subjects in long-term phase 3 trials and in 500 obese subjects without diabetes in a phase 2 trial (liraglutide up to 3 mg for up to 1 year).
a calcium stimulation test was performed in a sub-population of subjects
CT levels were within the normal range in all treatment groups throughout the treatment period, with no difference between liraglutide and active comparator at any point in time
No significant differences between treatments observed with stimulation test
calcitonin monitoring in humans
Hegedus L et al., J Clin Endocrinol Metab 2011
M Gallo Torino, 23 gennaio 2015
liraglutide e carcinoma (midollare?) della tiroide
M Gallo Torino, 23 gennaio 2015
“…based on the clinical safety database from the liraglutide development program and consistent with the nonclinical data, there is no suggestion of a link
between liraglutide exposure and the development of neoplasms in humans”
Liraglutide Analysis of Malignant Neoplasm Adverse Events
sconsigliato monitoraggio CT nei pazienti in terapia con liraglutide
riserve in pazienti con familiarità MEN2 o FMTC
…further long-term data are awaited…
M Gallo Torino, 23 gennaio 2015
Limits: • unpublished data? • subjects with established thyroid neoplastic and hyperplastic
lesions could have a different response to GLP-1R agonists aberrant GLP-1R expression detected in: 18% of human PTCs 27-50% of MTCs
• different responses in subjects with RET oncogene mutations? • longer duration of exposure?
Butler PC et al. Dia b Care 2013
M Gallo Torino, 23 gennaio 2015
• FDA AERS database – 2004-2009 – events with sitagliptin or exenatide vs.
rosiglitazone, nateglinide, repaglinide, or glipizide
• aumentato rischio: – pancreatite 6x – ca pancreas 2.7-2.9x – ca tiroide 4x (exenatide)
EASD: “…there is no definitive evidence pointing to an
increase in cancer risk. The only robust way of measuring comparative risk is within RCTs which record adverse events. There is no immediate need for action, and patients should under no circumstances stop taking any medication”
M Gallo Torino, 23 gennaio 2015
GLP-1 binding with GLP-1R: • induces insulin secretion from β-cells • promotes β-cells proliferation/differentiation • Inhibits β-cells apoptosis promoting effect on pancreas tumorigenesis?
M Gallo Torino, 23 gennaio 2015
Torino, 23 gennaio 2015
M Gallo Torino, 23 gennaio 2015
clinical trial program (2 years): – 5478 pts treated with dapaglifozin
• 9 breast cancers • 9 bladder cancers (all males)
– 3156 control: 1 breast + 1 bladder ca. not increased risk in animal studies (doses 100x) breast and bladder cells don't express SGLT-2
relatively high incidence of urinary tract infections role? detection bias?
“…The timing of the cases made it seem unlikely that dapagliflozin caused the cancers, although it may have accelerated them”
dapaglifozin, SGLT2-inhibitors, & cancer
Henry RR, ADA 71st Scientific Sessions 2011
M Gallo Torino, 23 gennaio 2015
Stumvoll & Nawroth, Diabetologia 2009
“patients are left alone trying to achieve a balance between the risks of unsatisfactory glucose control and media alerts on supposed increased cancer risks with the drugs they use”
“clinicians, on their part, have to venture into a challenging slalom between a healthy skepticism and the always lurking fear to harm, rather than to benefit their patients”
Gallo, Esposito, & Giugliano, Diab Res Clin Pract 2012
bladder cancer
breast cancer
thyroid cancer
CHF
pancreatic cancer
LDL-C
durability
hypos
HbA1c
weight
pioglitazone
glargine insulin
rosiglitazone
exenatide-sitagliptin
liraglutide
M Gallo Torino, 23 gennaio 2015
Preclinical or laboratory testing procedures are insufficient to confirm or to exclude potential cancer risks in humans
Prospective clinical trials are not feasible and are largely impracticable
Observational studies, due to their methodological limitations, cannot conclusively support a causal relationship
There is currently no definitive evidence that any diabetic medication (included insulin) has a causal, harmful effect on cancer development. Even if such a relationship were to be established, it would need to be weighed against the established benefits of these drugs.
trials…
M Gallo Torino, 23 gennaio 2015
How’s your attitude?
Torino, 23 gennaio 2015 Science. 2015 Jan 2
Torino, 23 gennaio 2015 M Gallo
1. Evaluate patient’s individual profile in terms of cancer risk
2. Assess cancer screening in our patients as routinely as for diabetes complications
3. Metformin
M Gallo Torino, 23 gennaio 2015
personalizzazione della terapia
• stile di vita
• acarbose
• metformina
• sulfoniluree
• glinidi
• glitazoni
• GLP-1
• inibitori DPP-IV
• Insulina
• Inibitori SGLT-2
• meccanismo d’azione
• FPG / PPG
• effetti sul peso
• effetti extra-glicemici
• reazioni avverse
• compliance
• efficacia (target?)
• costi
• durability
• età & durata di malattia
• comorbilità
• patologia CDV
• complicanze microvascolari
• rischio ipoglicemie
• autogestione/supporto sociale
• funzionalità d’organo
• condizioni psicologiche
• stato cognitivo
• rischio tumorale
Torino, 23 gennaio 2015 M Gallo Badrick E & Renehan AG; Eur J Cancer 2014